Comparative toxicity of netilmicin and gentamicin in squirrel monkeys (Saimiri sciureus).

Netilmicin was found to be less toxic than gentamicin when administered at comparable dosage levels to squirrel monkeys (Saimiri sciureus). This finding is based upon data obtained from the following determinations: length of survival period; change in body weight; observation of general change in behavior after daily injection; ataxia, as measured by the squirrel monkey platform-runway test; acoustic reflex threshold; levels of blood urea nitrogen and serum creatinine (and pathology of the kidney); and microbiological antibiotic assay.     

Plasma lipoprotein alterations in squirrel monkeys (Saimiri sciureus) during ethanol administration and abstinence

The time course of lipoprotein changes during ethanol (EtOH) consumption followed by abstinence was examined in 3 groups of male squirrel monkeys: 1) controls fed isocaloric liquid diet; 2) low EtOH monkeys given liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) high EtOH animals fed diet plus vodka at 24% of calories. After 2 weeks, high EtOH monkeys showed significant elevations in total plasma cholesterol which continued to increase at 4 weeks and then declined at 8 weeks. These elevations were the result of increases in both low density (LDL)- and high density lipoprotein (HDL)-cholesterol. Low EtOH monkeys had a modest increase in total cholesterol throughout 8 weeks which was attributed to increments in HDL-cholesterol alone. During abstinence, total, HDL- and LDL-cholesterol concentrations decreased rapidly in the high EtOH group and were similar to control values after 4 days. HDL-cholesterol showed a more gradual decline in animals fed 12% EtOH while LDL-cholesterol remained low and not significantly different from controls. Liver function tests were normal for all animals. Our results indicate that low-dose EtOH favors a coronary protective lipoprotein profile (increases HDL, decreases LDL) in squirrel monkeys while the higher alcohol regimen causes both favorable and unfavorable alterations in plasma lipids which quickly revert to control levels during abstinence.     

Hormonal response to stress in the squirrel monkey (Saimiri sciureus).

The pituitary-adrenal and gonadal responses following stress were evaluated in the squirrel monkey. Plasma levels of cortisol (CS), ACTH and testosterone (T) were determined during a 4-h period following the combined stress of capture and ether anesthesia. The results indicated that the squirrel monkey manifests higher basal levels of steroids than typically found in other mammals. The endocrine response following stress was biphasic, involving an initial elevation and subsequent decline in hormone levels. Males manifested significantly higher plasma levels of CS and T and lower plasma levels of ACTH than did females.     

The effects of light reinforcement and noise on young and old squirrel monkeys (Saimiri sciureus)

In two age groups of squirrel monkeys, subjects performed an operant response for light onset in the presence or absence of white noise. Results of the study indicate that light is an effective reinforcer for both younger and older monkeys, but differentially. The study also indicates that the presence of white noise affects responding in both age groups dissimilarly.     

Congenital Trypanosoma cruzi infection in a laboratory-born squirrel monkey, Saimiri sciureus

A Colombian Phenotype, laboratory-born squirrel monkey, Saimiri sciureus, was found to be congenitally infected with biologically proven Trypanosoma cruzi. The parasite was observed in blood smears and by xenodiagnoses of the mother and the offspring, and the isolates produced infection in mice and amastigotes in VERO tissue culture cells. The finding was accidental; both animals were healthy. Tissues of the mother did not show macro-microscopic evidence of T. cruzi infection and the electrocardiograph of the offspring was normal. This seems to be the first report of congenital T. cruzi transmission in an otherwise healthy non-human primate.     

Plasmodium inui and Babesia microti infections in the squirrel monkey, Saimiri sciureus

The course of Plasmodium inui and Babesia microti infections was studied in seven splenectomized squirrel monkeys (Saimiri sciureus) of Guyanan or Bolivian origin. Three of the monkeys were infected with P. inui either by the inoculations of parasitized blood or by the bite of infected mosquitoes. The remaining four monkeys were infected by the inoculation of parasitized blood, containing P. inui and B. microti in three and with B. microti only in one. The infection in all seven animals was severe, terminating fatally.     

HTLV type 1 infection in squirrel monkeys (Saimiri sciureus): a promising animal model for HTLV type 1 human infection

We show that the squirrel monkey Saimiri sciureus is susceptible to experimental infection with either syngeneic or allogeneic HTLV-1-immortalized cells. As in humans, such experimental inoculation leads to chronic infection, and HTLV-1 provirus was detected in PBMCs by PCR. Chronically infected monkeys developed high titers of antibodies against the structural proteins of the virus, as do HTLV-1-infected humans. Furthermore, in serially sacrificed squirrel monkeys infected with HTLV-1, proviral DNA was detected at primary phases of infection in PBMCs, spleens, and lymph nodes. Tax/rex mRNA was also detected by RT-PCR in the PBMCs of two monkeys at 12 days after inoculation and in the spleen and lymph nodes of the monkey sacrificed on Day 12. In this animal, scattered HTLV-1-tax/rex mRNA-positive lymphocytes were detected by in situ hybridization in frozen sections of the spleen. These results indicate that PBMCs, spleen, and lymph nodes serve as major reservoirs for HTLV-1 during the early phase of infection. To evaluate the relationship between viral expression and the immune response during infection, humoral and cytotoxic T cell responses (CTL) were studied at various times after inoculation. Antibodies to HTLV-1 were detected 3 weeks after infection and anti-p40Tax and anti-Env CTL activity was detected 2 months after infection and remained detectable thereafter. Our results indicate that the squirrel monkey provides a useful animal model for studying the pathogenesis of HTLV-1 and for evaluating new candidate vaccines.     

Chemotherapy of visceral leishmaniasis (Leishmania donovani) in the squirrel monkey (Saimiri sciureus)

The relationship of the numbers of amastigotes in the liver to the duration of infection with two lines of a Khartoum strain of Leishmania donovani [designated the parent (P) line and the meglumine antimoniate (Glucantime) resistant (MAR) line] and the effect of meglumine antimoniate on these two lines of Leishmania were studied in the squirrel monkey. All experimental monkeys were inoculated via the saphenous vein with 32.5 X 10(6) amastigotes (per kg body weight), obtained from heavily-infected hamster spleens. Subsequently in Experiment I, liver biopsy samples were taken chronologically from all monkeys. Imprints of liver were made on glass slides and stained with Giemsa's staining solution, and parasite density per gram of liver tissue was determined. The parasites reached a maximum density of 6.2 X 10(6) amastigotes per gram between two to four weeks and 9.4 X 10(7) amastigotes per gram between four to six weeks in the monkeys receiving the P line and the MAR line, respectively. Parasite numbers then decreased, and all the livers and spleens of all monkeys became microscopically negative for Leishmania eight to 13 weeks post-infection. Comparison of the multiplication of the two lines of Leishmania indicated that the MAR line persisted longer in the livers than did the P line. A slight decrease in body weight was observed at eight weeks post-infection. Packed cell volume and haemoglobin were low at four to eight weeks post-infection, but were within the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inheritance of color vision in a New World monkey (Saimiri sciureus).

Squirrel monkeys (Saimiri sciureus) have a striking color-vision polymorphism; each animal has one of six different types of color vision. These arise from individual variation in the presence of three different middle- to long-wavelength cone pigments. The distribution of cone phenotypes was established for a large sample of squirrel monkeys, including several families, through analysis of a retinal gross potential. The results indicate that the inheritance of color vision in the squirrel monkey can be explained by assuming that the three middle- to long-wavelength cone pigments are specified by three alleles at a single locus on the X chromosome. This arrangement is discretely different from that found in Old World monkeys and humans.     

Urinary steroid excretion by the squirrel monkey (Saimuri sciureus).

Urinary steroids and steroid conjugates were measured in the squirrel monkey (Saimuri sciureus). The principal steroids excreted were cortisol, 11beta,17alpha,20beta,21-tetrahydroxy-4-pregnen-3-one (20beta-dihydrocortisol), alpha- and beta-cortol and alpha- and beta-cortolone. The majority of the steroids were excreted unconjugated and a conspicuous feature of the pattern was the large amount of urinary free cortisol. Unlike man there was an insignificant excretion of 3alpha,17alpha,21-trihydroxy-5beta-pregnane-11,20-dione (tetrahydrocortisone) and 3alpha,11beta,17alpha,21-tetrahydroxy-5beta-pregnan-20-one (tetrahydrocortisol). A steroid not previously identified in urine from any species was one of the major glucuronide conjugates; it was characterized as having the structure 3beta,17alpha,20xi,21-tetrahydroxy-5beta-pregnan-11-one. Administration of dexamethosone resulted in complete suppression of steroid output, whilst the response to adrenocorticotrophic hormone was inconstant.     

Pathologic changes associated with fatal Plasmodium falciparum infection in the Bolivian squirrel monkey (Saimiri sciureus boliviensis)

Fatal cases of experimental Plasmodium falciparum (Indochina I) in Bolivian squirrel monkeys (Saimiri sciureus boliviensis) were examined by histologic and ultrastructural methods. Gross lesions were characterized by hepatosplenomegaly and interstitial pulmonary changes. Histologically, there was marked diffuse reticuloendothelial hyperplasia, pulmonary alveolar septal thickening, mesangioproliferative glomerulonephropathy, sequestration of parasitized erythrocytes in deep vascular beds, degenerative parenchymal changes in the liver and myocardium, and in one case retinal and cerebral hemorrhage. These data indicate that the Bolivian squirrel monkey is a good model for studying pathologic changes associated with human falciparum malaria.     

Metabolism of [125I]tyramine cellobiose-labeled low density lipoproteins in squirrel monkeys

Low density lipoproteins labeled with [125I]tyramine cellobiose ([125I]TC-LDL) were removed from the circulation of squirrel monkeys at a similar but slightly slower rate than LDLs labeled with 125I, [125I]hydroxyphenyl propionic acid, or [3H]leucine. After the simultaneous injection of [125I]TC-LDL and [131I]LDL labeled with 131ICl, the 125I was also removed at a slightly slower rate than 131I. Most of the radioactivity was retained in tissues and not excreted during the 24 h after injection of [125I]TC-LDL. This finding supports the claim of Pittman et al. [18] that [125I]TC-LDL can be used to determine the irreversible uptake of LDL by different tissues. The liver cleared more LDL than any other organ, but the adrenals and ovaries were more active per gram. Trichloroacetic acid (TCA) precipitated more than 80% of the radioactivity in the tissues that had low 125I uptake, but only about 50% of the 125I in more active tissues (liver, adrenals, ovaries, and spleen). Only a small percentage of 125I in urine and bile was TCA-precipitable. In the dual label experiment with [125I]TC-LDL and [131I]LDL there was a selective retention of 125I in samples from liver, spleen, adrenals, and, perhaps testes, and an almost complete selectivity for 125I in bile and feces. The aortic intima plus inner media (AIM) cleared much less LDL than other tissues, but the uptake by the entire AIM was proportional to the cholesterol concentration and weight of the total AIM. There was, however, no correlation between either of the latter two measurements and the uptake of LDL per gram of AIM. The concentration of LDL apolipoprotein in the AIM determined by immunoelectrophoresis did not correlate significantly with LDL uptake per gram. Both the amounts of LDL apolipoprotein present and labeled LDL taken up by the AIM depended on the weight of the sample, and perhaps on the weight of intima in the sample.     

Biodistribution of 131I-radiolabelled plasma low density lipoprotein in hyperlipidaemic vervet monkeys

Low density lipoprotein (LDL) labelled with 131I has been administered to 6 Vervets 2 of which were high responders to an atherogenic Western diet in terms of plasma cholesterol, 2 were low responders and 2 were fed a high carbohydrate control diet. The ratio of hepatic to cardiac activity was recorded for up to 10 days after administration of the labelled LDL. Liver activity had a longer biological half life in the high-responders and this can be interpreted in terms of a variation of hepatic metabolism of LDL, with direct relevance to the human situation.     

Protective antibodies against erythrocytic stages of Plasmodium falciparum in experimental infection of the squirrel monkey, Saimiri sciureus

Serum and ascitic fluid from squirrel monkeys ( Saimiri sciureus ) inoculated with erythrocytic stages of Plasmodium falciparum were collected at different periods of the infection. Protection against P. falciparum was achieved by passive transfer of the sera or fluid recovered from animals after spontaneous or drug-induced cure. Purified immunoglobulins from the ascitic fluid also conferred protection. In contrast, protective antibodies directed against erythrocytic stages of P. falciparum could never be demonstrated during the acute phase of infection in spite of the high titres of malarial antibodies detected by immunofluorescence. The comparative immunochemical analysis of antigens recognized by protective and non-protective antibodies revealed quantitative differences which may be of use for the identification of antigens inducing protection.     

Plasma low density lipoprotein composition in relation to atherosclerosis in nutritionally defined Vervet monkeys

An atherogenic diet (AD) consisting entirely of normal foods for westernized people was fed to female Vervet monkeys for 4 years. The plasma low density lipoprotein (LDL) cholesterol pool was increased and progression of atherosclerosis was enhanced by the AD compared to a more prudent Western diet. The increased LDL-cholesterol was carried by a 3-fold increase in particles of relatively normal composition and not by packing cholesterol esters into the cores of enlarged LDL particles, as has been reported after feeding semisynthetic diets loaded with extra cholesterol. Nevertheless, these LDL particles were atherogenic. The AD changed the fatty acid composition of LDL-cholesterol esters and triacylglycerol, notably by increasing arachidonic and reducing linoleic acid. Multivariate analysis showed that measures and scores of atherosclerosis were significantly dependent on sphingomyelin and phosphatidylcholine in LDL and on arachidonic acid in LDL-triacylglycerol. Although apolipoprotein B, free cholesterol, esterified cholesterol and lysophosphatidylcholine in plasma LDL and atherosclerosis were significantly positively correlated in bivariate analysis they were not selected by multivariate analysis as the strongest determinants of atherogenesis. Cholesterol in plasma high density lipoprotein was not changed by the AD and lecithin:cholesterol acyltransferase activity in plasma was inversely linked to atherosclerosis. Subcutaneous fatty acids reflected dietary fatty acids.     

Influence of early diabetic nephropathy on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition.

The procedure of discontinuous gradient ultracentrifugation (DGU) was used to characterize the influence of early diabetic nephropathy on the composition of very low density lipoprotein (VLDL, flotation density 60-400 Svedberg (Sf) units), low density lipoprotein (LDL, flotation density 0-12 Sf) and subfractions of intermediate density lipoprotein (IDL1 and IDL2, 20-60 and 12-20 Sf, respectively). Forty-six subjects with type 1 (insulin-dependent) diabetes and serum creatinine, less than 140 mumol/l were studied, of whom 23 consistently had normal rates of albumin excretion (AER less than 15 micrograms/min), and 23 had persistent albuminuria (AER 20.0-960.6 micrograms/min). The two groups were similar with respect to total serum lipids, glycaemic control, age and body mass. The composition (lipid, protein and phospholipid) and mass of VLDL, LDL and IDL2 was not appreciably altered by early nephropathy, but free and total cholesterol concentration in IDL1 (Sf 20-60) was increased (total cholesterol 0.68 (0.09) (mean (SE)) vs. 0.47 (0.07) mmol/l, and free cholesterol 0.27 (0.04) vs. 0.17 (0.03) mmol/l, both P less than 0.05). The explanation of these findings was probably an accumulation in the circulation of the remnants of chylomicron metabolism and/or intermediates in the conversion from VLDL to IDL1. In addition, there was a decrease in serum high density lipoprotein (HDL) cholesterol in early nephropathy (1.27 (0.06) vs. 1.38 (0.10) mmol/l, P less than 0.05), due to a decrease in the HDL2 cholesterol subfraction (P less than 0.05). These findings may in part explain the increased risk of premature atherosclerosis associated with the development of albuminuria.     

Apolipoprotein A-I and apolipoprotein B containing lipoprotein particles in coronary patients treated with extracorporal low density lipoprotein precipitation (HELP).

Evidence for chemical and biological heterogeneity of human plasma lipoprotein density classes has been steadily accumulating over the last 15 years. Furthermore, several recent reports have indicated potential clinical significance of certain lipoprotein subspecies as either atherogenic or antiatherogenic. It is generally accepted that lipid lowering treatments can retard or even reverse development of atherosclerotic lesions. However, very little is known about effects of various lipid lowering treatments on specific lipoprotein particles. The purpose of this study was to explore the effects of heparin induced extracorporal low density lipoprotein precipitation (HELP) on various subspecies of plasma lipoprotein particles defined primarily by their apolipoprotein composition. Using particle specific enzyme immunoassays, the immediate changes in lipoprotein particle profiles were analyzed after a single HELP treatment in 12 patients with angiographically documented coronary artery disease. In a separate group of 6 patients, particles were repeatedly measured over a period of 96 h following a HELP treatment. Single HELP treatment caused an immediate and highly significant decrease (67%) in the concentration of simple lipoprotein particles containing apolipoprotein B (apo B) as a sole apolipoprotein (LP-B). Various subspecies of complex particles containing apo B and other apolipoproteins (Lp-B-complex) were also decreased although to a lesser degree (44-53%). HELP treatment caused an insignificant, 3% decrease of lipoprotein particles containing apo A-I but no apo A-II (Lp-A-I) and a 6% decrease in the concentration of particles containing both apo A-I and apo A-II (Lp-A-I:A-II). During the 96-h period following HELP treatment various apo B containing particles recovered at different rates in different patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Integrated study of low density lipoprotein metabolism and very low density lipoprotein metabolism in non-insulin-dependent diabetes

The metabolisms of VLDL, IDL, and LDL and their interconversions have been studied in ten obese untreated male Pima Indian diabetics compared to 16 age-, sex-, and weight-matched nondiabetics. VLDL was elevated in the diabetics and had abnormal composition, as indicated by a significantly higher ratio of triglyceride/apo B. Fractional catabolic rates for both VLDL apoB and VLDL triglyceride were lower in diabetics, and diabetics had increased production of VLDL triglyceride but not VLDL apoB compared to obese nondiabetics. A higher proportion of VLDL apoB was removed without conversion to LDL in diabetics. LDL cholesterol and apoB were higher in diabetics, but production of LDL apoB was not different from nondiabetics. Fractional catabolic rate for LDL apoB, however, was significantly lower in the diabetics. The data indicate that the triglyceride-rich VLDL in non-insulin-dependent diabetics are less readily converted to LDL, whereas the elevated LDL in this group of diabetics is due to impaired clearance. Thus, decreased conversion of VLDL to LDL and impaired LDL clearance are two opposing phenomena which may influence the LDL concentration of diabetics in either direction. Thus, despite minimal changes in LDL concentration, there are multiple defects in the metabolism of LDL in non-insulin dependent diabetes which may contribute to the increased atherogenesis in this disorder.